IL-1β stimulates a novel, IKKα -dependent, NIK -independent activation of non-canonical NFκB signalling

McIntosh, Kathryn; Khalaf, Yousif H.; Craig, Rachel; West, Christopher M.; McCulloch, Ashley; Waghmare, Ajay; Lawson, Christopher E.; Chan, Edmond Y W; Mackay, Simon P.; Paul, Andrew; Plevin, Robin

doi:10.1016/j.cellsig.2023.110684

Cited by 3 publications

(1 citation statement)

References 42 publications

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“…NIK regulation involves dynamic ubiquitination and proteasome degradation mediated by TRAF3, and the TRAF-cIAP E3 complex serves as a NIK ubiquitin ligase. Additionally, some viral oncoproteins, like Tax and vFLIP, can induce p100 processing independently of NIK by interacting with p100 and IKKa, potentially activating IKKa through different mechanisms [20,21]. Other signalling pathway NF-κB regulation is complex, involving activation through canonical cytokine pathways and multiple signal transduction cascades related to cardiac hypertrophy and oxidative stress responses.…”

Section: Non-canonical Nf-κb Pathwaymentioning

confidence: 99%

UNLOCKING THE THERAPEUTIC POTENTIAL: EXPLORING NF-κB AS a VIABLE TARGET FOR DIVERSE PHARMACOLOGICAL APPROACHES

SINGH,

SHARMA,

SINGH

2024

Int J Pharm Pharm Sci

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NF-κB is a vital transcription factor that responds to diverse stimuli like cytokines, infections, and stress. It forms different dimers, binds to specific DNA sequences, and regulates gene expression. It operates through two pathways: canonical (for inflammation and immunity) and non-canonical (for specific processes). These pathways tightly control activity of NF-κB and impacting gene expression. Aberrant NF-κB activation is linked to cancer and other diseases, making it a potential therapeutic target. This review explores the role of NF-κB in disease and its therapeutic potential in various conditions. Intricate signal transduction processes lead to NF-κB activation by phosphorylating IκB proteins, allowing NF-κB dimers to enter the nucleus and influence gene expression. This dynamic regulation involves co-activators and interactions with other transcription factors, shaping complex gene expression programs. Understanding the multifaceted functions off NF-κB is crucial as its deregulation is associated with a range of diseases, including cancer, autoimmune disorders, and inflammatory conditions. Exploring recent studies offers insights into potential therapeutic strategies aimed at modulating NF-κB activity to restore health and combat various pathological conditions. This Comprehensive review is based on the role of NF-κB in disease pathogenesis and therapeutic implications.

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Section: Non-canonical Nf-κb Pathwaymentioning

confidence: 99%

UNLOCKING THE THERAPEUTIC POTENTIAL: EXPLORING NF-κB AS a VIABLE TARGET FOR DIVERSE PHARMACOLOGICAL APPROACHES

SINGH,

SHARMA,

SINGH

2024

Int J Pharm Pharm Sci

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Antioxidant synergistic anti‐inflammatory effect in the MAPK/NF‐κB pathway of peptide KGEYNK (KK‐6) from giant salamander (Andrias davidianus)

Zhan,

Wu,

et al. 2024

J Sci Food Agric

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BACKGROUNDGiant salamander protein peptide is a peptide with rich functional properties. Giant salamander protein peptide KGEYNK (KK‐6) is a peptide with both antioxidant and anti‐inflammatory properties. The antioxidant and anti‐inflammatory mechanisms of KK‐6 are still unclear. When we studied the functional mechanism of KK‐6, we found that the antioxidant property of KK‐6 has a synergistic and promoting effect on anti‐inflammatory properties.RESULTSKK‐6 enhances cellular resistance to LPS via the MAPK/NF‐κB signaling pathway, leading to increased levels of inflammatory factors: interleukin‐1β (764.81 ng mL−1), interleukin‐6 (1.06 ng mL−1) and tumor necrosis factor‐α (4440.45 ng mL−1). KK‐6 demonstrates potent antioxidant properties by activating the Nrf2 signaling pathway, resulting in elevated levels of antioxidant enzymes (glutathione peroxidase: 0.03 μg mL−1; superoxide dismutase: 0.589 μg mL−1) and a reduction in the concentration of the oxidative product malondialdehyde (967.05 μg mL−1).CONCLUSIONOur findings highlight the great potential of KK‐6, a peptide extracted from giant salamander protein, as a remedy for intestinal inflammation. Through its dual role as an antioxidant and anti‐inflammatory agent, KK‐6 offers a promising avenue for alleviating inflammation‐related damage and oxidative stress. This study lays the foundation for further exploration of giant salamander products and highlights their importance in health and novel food development. © 2024 Society of Chemical Industry.

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Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling

Riley,

Ammar,

Alsfouk

et al. 2024

Molecules

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The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo[2,3-b]pyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure–activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 [IKKα Ki = 10 nM; IKKβ Ki = 680 nM] and SU1349 [IKKα Ki = 16 nM; IKKβ Ki = 3352 nM]) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents.

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IL-1β stimulates a novel, IKKα -dependent, NIK -independent activation of non-canonical NFκB signalling

Cited by 3 publications

References 42 publications

UNLOCKING THE THERAPEUTIC POTENTIAL: EXPLORING NF-κB AS a VIABLE TARGET FOR DIVERSE PHARMACOLOGICAL APPROACHES

UNLOCKING THE THERAPEUTIC POTENTIAL: EXPLORING NF-κB AS a VIABLE TARGET FOR DIVERSE PHARMACOLOGICAL APPROACHES

Antioxidant synergistic anti‐inflammatory effect in the MAPK/NF‐κB pathway of peptide KGEYNK (KK‐6) from giant salamander (Andrias davidianus)

Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling

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